Midlife provides an invaluable baseline for changes associated with aging, but is rarely a focus of brain aging studies. We will perform a longitudinal MRI study of middle-aged twins focusing on distributed neural circuits comprising prefrontal cortex (PFC) and associated subcortical structures, and the hippocampus. These regions show significant age-related change and are linked to cognitive functions (executive functions, episodic memory) that are particularly important in aging. We will conduct comprehensive volumetric analyses, emphasizing parcellation of PFC and highly detailed analysis of hippocampal subregions. We will also measure cortical thickness, white matter hyperintensity volumes, generate cerebral blood volume and T2*-weighted maps of hippocampal subregions to index static neuronal function, and perform diffusion tensor imaging to examine the microstructural integrity of white matter. Evidence to date suggests that the latter 2 techniques may detect age related differences or predict future impairment even in the absence of volume changes. The proposed study builds on our funded "Longitudinal Twin Study of Cognition and Personality"-a single integrated project comprising 2 grants (AG 18386-012A1 & A2)-which we refer as the Vietnam Era Twin Study of Aging (VETSA). The VETSA is assessing 720 middle aged twin pairs from the Vietnam Era Twin Registry (1/2 in Sacramento, 1/2 in Boston); 360 pairs at age 51+/-1 and 360 pairs at age 56+/-1. The design calls for follow-up every 5 years. Assessments include a neurocognitive battery (working memory, cognitive inhibition, processing speed, episodic memory), personality/psychosocial measures, and health/medical measures (BP, ankle-ann index, pulmonary function, genotyping). Based on a broad conceptual model, the goals are to use the twin method to determine the extent of genetic factors, shared environmental factors, and unique environmental factors influencing these variables, and to explicate the bases of inter-relationships within and among domains using bivariate, multivariate, and longitudinal twin analytic approaches. Key advantages are beginning in midlife (before substantial age-related declines), and having only 2 large, narrow age cohorts to maximize power to detect within-person change over time. The proposed study will begin in VETSA year 2 and will have 300 of the VETSA twin pairs undergo MRIs. We will examine genetic and environmental influences on our MRI measures in midlife as well as their association with key VETSA measures in both longitudinal and cross-sectional analyses. We will also create a normative database-a library of scans-that will provide a unique and valuable resource for future researchers.